Tosylates And Mesylates

Today we’re going to talk about a different way of making alcohols into good leaving groups – by turning them into tosylates and mesylates (“organosulfonates”). Here’s a brief summary of what we’ll cover here:

Making Alcohols Into Good Leaving Groups, Part 2

We’ve seen that alcohols are poor substrates for substitution reactions. The main problem is that the hydroxyl group is a strong base, and thus a poor leaving group.

In the last post we saw that we can convert alcohols into alkyl halides by adding strong hydrohalic acids (HCl, HBr, HI): the strong acid protonates R-OH to give R-OH2+ (with the better leaving group, H2O) and then substitution by the halide ion can occur.

In contrast to alcohols, alkyl halides are GREAT substrates for nucleophilic substitution reactions.

Unfortunately this doesn’t always work well. There are two main problems. First of all, on certain secondary alcohols the reaction proceeds through an SN1 pathway, which can lead to rearrangements. Secondly, in so doing, we can end up scrambling any stereocenters that are present. For instance if we start with one enantiomer in the reaction below, we end up with some racemization of the final product.

So is there some other way to convert alcohols into good leaving groups that doesn’t have these problems?

Sure thing!

One Good Idea (Which Doesn’t Actually Work That Well)

We all know that hydroxide (HO- ) is a strong base. But have we seen any examples of weak bases with a negative charge on the oxygen?

Yes! Sulfuric acid (H2SO4) is a very strong acid (pKa of about -3) and its conjugate acid, -OSO3H , is therefore a weak base. This is due to two key factors – first of all, delocalization of charge on the other oxygens through resonance, and secondly, the inductive effect of those oxygens helping to redistribute the charge.

So in a perfect world, if we had some way of easily turning an alcohol (R-OH) into an alkyl hydrogen sulfate (R-OSO3H) then we’d have a nice way of making an alcohol into a good leaving group.

So how might this work in practice? Actually it doesn’t work very well!

It’s not that –OSO3H is a poor leaving group (it’s a great leaving group). The problem is that many nucleophiles are quite basic (remember – the conjugate base is a better nucleophile) and the OSO3H still has a very acidic proton (that OH group has a pKa of about 2, making it a stronger acid than acetic acid).

The bottom line is that if we add a basic nucleophile, an acid base reaction will occur instead of our desired substitution reaction. The nucleophile will be protonated into its conjugate acid (less nucleophilic) and any substitution reactions will be considerably slower. Not ideal!

Introducing “Tosylates” and “Mesylates”

Is there some way around this? Sure! It’s just a matter of replacing that OH group on the sulfur by some kind of relatively inert organic group (R group) that doesn’t have an acidic proton.

If we swap in a methyl group (CH3) our leaving group would be –OSO2CH3, or “methanesulfonate” (commonly called, “mesylate” and abbreviated OMs. This has all the advantages of a great leaving group without the drawback of an acidic proton to react with nucleophiles.

Another popular option is using the conjugate base of p-toluenesulfonic acid, (“p-toluenesulfonate”) commonly called “tosylate” and abbreviated OTs.

These groups have essentially identical leaving group ability and for our purposes are interchangeable. Some textbooks tend to use Ts more, others use Ms. It doesn’t really matter for us at this stage: they both work.

[A third option, less commonly seen in introductory courses, is the “triflate” (Tf) group, which replaces the three hydrogens on methanesulfonate with three fluorines. The conjugate acid, trifluoromethanesulfonic acid, is among the more acidic species known (pKa of -13!) and for this reason, triflate is a really “hot” leaving group when attached to alkyl groups: it likes to leave of its own accord! It’s more commonly used on aromatic alcohols and other species that don’t form carbocations as easily]

How Do We Make Mesylates And Tosylates From Alcohols?

So how can we apply this? If we have an alcohol, how do we turn that hydroxyl into a tosyl or mesyl group?

It’s relatively straightforward actually. We use “mesyl chloride” (MsCl) or “tosyl chloride” (TsCl), and the neutral alcohol performs a substitution reaction on sulfur, leading to formation of O-S and breakage of S-Cl. Then, deprotonation of the charged alcohol leads to the neutral mesylate or tosylate.

Note that the stereochemistry is completely unchanged here (unlike if we had used H-Cl, for example). Watch out for this – stereochemistry is often tested on exams!

[By the way – sometimes you might see that an organic base such as pyridineis also added, which helps the process along by removing HCl as it is formed. ]

Specific Examples

Let’s finish up by seeing some specific examples of Ts and Ms in action. As they contain a good leaving group, alkyl tosylates or mesylates can perform all of the substitution and elimination reactions of alkyl halides. A few examples are shown below. Get familiar with MsCl and TsCl in both their abbreviated and expanded (i.e. “drawn-out”) forms.

Next time…

In the last two posts we’ve seen how useful it is to be able to convert alcohols to good leaving groups. In our next post we’ll cover one last method to do this that involves some new reagents, PBr3 (including other phosphorus halides) and SOCl2.

Thanks Brandon!
I didn’t want to go into the nitpicky details, but my understanding is that NEt3 and stronger bases will generate the sulfene, while pyridine and other similar bases (like DMAP) will add to the sulfur and create an activated, charged intermediate (like DMAP+acyl halide) which is then attacked by the alcohol. [that’s why I left pyridine out of the mechanism : – ) ]

My understanding is that pyridine/DMAP acts as both base and nucleophile. The base character generate the sulfene, which is then attacked by a second molecule of pyridine/DMAP to form the charged intermediate you’re referring to (this step also deprotonates the first unit of pyridine/DMAP).

The nature of the reaction could change depending on the type of sulfonyl chloride. For example, t-burylsulfonyl chloride can’t form the sulfene, and must react via either SN1 or SN2. It’s also an incredibly poor electrophile, to the point where it does not react with amines under standard conditions, necessitating a weird oxidation from the sulfinamide to make t-butylsulfonamide.

My friend Jeff who did some research proposals on sulfenes is of the opinion that DMAP might be a strong enough base to form the sulfene, whereas pyridine is not.
“I think that DMAP probably would go via the sulfene. It’s basicity is closer to NEt3 than it is to pyridine and in organic solvents it may even be more basic: accordingly to Wikipedia, pKb of DMAP in MeCN is 17.95 (Couldn’t easily find the DMSO value). TEA in DMSO is 9, while pyridine is 3.4 in DMSO.”

Truly great post! One small thing, though: in the text there appears “trifluoromethylsulfonic acid”, which I thing should read “trifluoromethanesulfonic acid”, as it actually does in the picture below the paragraph.

I have one problem, my compound is open sugar molecule, I have to tosylate selectively the primary alcohol. I have try the pyridine as a base, but I am not able to get the product. Please give your suggestion.

I would selectively tritylate the primary alcohol with trityl chloride, protect the other alcohols with acetic anhydride or TBS, remove the trityl group with trichloroacetic acid, then convert the primary alcohol into a tosylate with TsCl.

Hi, thank you for nice explanations! Got a question… Is it will be a problem for mesilation of free OH, if i have another hydroxyl in the compound already protected with trityl group? I just need farther convert mesyl into azide, since it well leaving group. And need to keep other primary OH protected during this pricedure. Any advise please! Thank you!

Thiols and amines (but particularly amines) can react with MsCl and TsCl. For that reason, when one is trying to synthesize a given molecule it is important to only have one reactive functional group present and have the others deactivated through protection. Trying to selectively tosylate or mesylate a molecule that has multiple unprotected functional groups is a recipe for a lot of wasted time.

I’m not completely sure about the question being asked.
If the question is: “if you have an alcohol and an amine on a molecule, which one will react with TsCl first?”
The answer to that is, the amine, by a large margin because amines are many orders of magnitude more nucleophilic.
It is relatively difficult to remove a Ts group from nitrogen, therefore it is not recommended as a protecting group.
If you could clarify your question then I could try to answer it differently.